A component of the nuclear substructure, A-type lamins (encoded by LMNA), are targets for mutation in a range of diseases termed laminopathies. The most commonly occurring affect skeletal muscle and cardiac function, with LMNA mutations resulting in muscular dystrophy (EDMD2/3 and LGMD1B) and dilated cardiomyopathy with conduction defects (CMD1A). The molecular mechanisms causing pathology in these diseases are poorly understood. In preliminary studies, we find that tissues from mice lacking A-type lamins exhibit elevated mTOR signaling that contributes to pathology. The fundamental goals of this proposal are to determine the mechanistic links between altered A-type lamin function, elevated mTOR activation and cardiac disease. The central hypothesis is that A-type lamin's function at the nuclear periphery is important for controlling signal transduction pathways that in turn impact mTOR activation. Aim 1 is devoted to connecting signaling pathways leading from reduced lamin A/C expression to enhanced mTOR signaling, focusing on MAP kinase activation as a potential link. In the second Aim, I describe experimental approaches to determine the consequences of aberrantly elevated mTOR signaling in cardiac and skeletal muscle tissue, focusing on a novel microRNA (miRNA) pathway that we have identified. Lastly, the efficacy of rapamycin in two other mouse models that more closely resemble human pathology will be examined.